The principal objective of our project is to improve the health of children with Human Immunodeficiency Virus-1 (HIV) and Mycobacterium tuberculosis (M. tb) co-infection by accurately identifying those infected with M. tb. The study was designed to examine the utility and interpretation of Interferon-Gamma Release Assays (IGRA) in children with M.tb and HIV co-infection. There are limited data on the use of IGRA to detect M. tb infection in HIV-infected children/In a prospective community-based study in a setting highly endemic for tuberculosis (TB) and HIV, the following specific aims will be addressed in HIV-infected (N=300) and uninfected (N=500) children [unreadable]5 years of age: 1) asses the agreement between the traditional tuberculin skin test (TST) and IGRAs, 2) assess the performance of the TST and IGRAs across a standard gradient of M. tb exposure, 3) measure the impact of potential interaction and confounding variables and 4) identify factors that modify children's response to TST and IGRA over time. We will utilize a community-based controlled TB household contact study design to describe both household and community M.tb exposure and infection through a standardized gradient of M.tb exposure (contact score). The standardized M. tb contact score will be a composite measure of the index case infectivity and the child's proximity and duration of contact with the TB index case. A focused set of standardized measures of age, nutrition and HIV-related immune status (CD4 T lymphocyte count) will be collected to fully assess their effect on the TST and IGRAs. Longitudinal analysis will also measure the influence of additional modifiers including time since exposure, anti-retroviral therapy, HIV viral load and isoniazid therapy. The proposed study involves primary data collection that wi-l address important gaps in our current knowledge regarding the utility and specific applicability of IGRAs for detection of M. tb infection in HIV-infected children. This includes identification of optimal cut-off values for interpretation of IGRAs in HIV-infected and -uninfected children in highly endemic settings. In HIV-infected children, those most vulnerable to TB-related morbidity and mortality IGRAs may assist in optimal clinical management through accurate and timely diagnosis and targeted preventive or curative therapy. Accurate diagnostic tools will also limit over diagnosis and treatment. Hence, IGRAs have great potential to improve TB control and decrease HIV-TB related disease and deaths in children. LAY DESCRIPTION: Novel Interferon Gamma Releases Assays have great potential to improve TB control and decrease HIV-TB related disease and deaths in children. However, it is imperative that the utility and interpretation of these tests be studied in HIV-infected children in settings with high burdens of TB and HIV.